Selective serotonin receptor antagonists and therapeutic applications thereof

ABSTRACT

Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (SPAN) and derivatives thereof are provided as selective serotonin receptor antagonists. The compounds are selective, high affinity antagonists of 5-HT 2  serotonin receptors. The compounds are useful as antidepressant and antianxiety agents.

[0001] This invention was made using funds from grants from the NationalInstitutes of Health having grant number MH57969. The government mayhave certain rights in this invention.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention generally relates to selective serotonin receptorantagonists and methods of their use as antidepressant and antianxietyagents. In particular, the invention providesspiro[9,10-dihydroanthracene]-9,3′-pyrrolidine (SPAN) and derivativesthereof as selective high affinity antagonists of 5-HT receptors.

[0004] 2. Background of the Invention

[0005] Serotonin (5-hydroxytryptamine, or 5-HT; see Formula 1) is aproduct of tryptophan metabolism that mediates many diversephysiological activities. Most fundamentally, this well-characterizedtryptamine derivative functions as a potent neurotransmitter byregulating G-protein coupled and ligand gated ion channel receptors atthe surface of nerve and muscle cells. This activity is mediated by thebinding of serotonin to several classes of cell-surface 5-HT receptors.Numerous 5-HT receptors are known and have been categorized into severalfamilies (5-HT₁-5-HT₇) and some are further divided into subfamilies(e.g. 5-HT_(2A) and 5-HT_(2C)). Many of the 5-HT receptors have beencloned and their specific functions elucidated.

[0006] Imbalances in serotonin activity are believed to be responsiblefor a variety of clinically recognized disorders. For example, manybrain disorders in humans are associated with fluctuations in serotoninlevels and are effectively treated with drugs that interact specificallywith 5-HT receptors or that block the reuptake of serotonin into thepresynaptic axon terminals, suggesting that serotonin dysregulation maybe involved in these disorders. For example, serotonin receptor ligandsare clinically approved as drugs for the treatment of depression,psychosis, anxiety, and certain sexual aberrations, as well as for otherconditions such as migraine headaches, chemotherapy-induced nausea, highblood pressure, certain abnormal cardiovascular activities and abnormalthermoregulation.

[0007] However, most of these existing agents are relativelynonselective in that they exhibit affinities for several 5-HT receptorclasses, as well as for central dopaminergic, noradrenergic,histaminergic, and/or cholinergic receptors, as well as blockingserotonin and dopamine reuptake into the nerve terminus. As aconsequence of activity at nonserotonergic sites, the use of theseagents may result in undesirable side effects such as tardivedyskinesia, tardive dystonia, excessive weight gain, etc. These sideeffects can be debilitating and may require clinical treatment in and ofthemselves. The possibility of the occurrence of side effects is a causeof distress to patients, and is a likely contributor to patientnon-compliance with suggested drug therapy regimens.

[0008] Ligands which bind with varying degrees or selectivity to somefamilies of 5-HT receptors are known. For example, U.S. Pat. Nos.5,496,957 and 5,504,101 to Glennon (Mar. 5, 1996 and Apr. 2, 1996,respectively, the complete contents of which are hereby incorporated byreference) describe agents which bind to the 5-HT_(1Dβ) receptor. AndU.S. Pat. No. 5,942,536 to Fritz et al. (Aug. 24, 1999, the completecontents of which is hereby incorporated by reference) describes agentswhich bind to the 5-HT_(1f) receptor. Roth et al. (1994) describe thebinding affinities of 36 typical and atypical antipsychotic agents to5-HT₆ and 5-HT₇ receptors, and Glennon et al. (1989) describe classes ofagents which bind to 5-HT_(1A) receptors. Finally, Glennon et al. (1994)describe the effect of different amine substitutions on phenylalkylamineand indolylalkylamine derivatives which bind to 5-HT_(2A) and 5-HT_(2C)serotonin receptors. There is an ongoing need for the development ofalternative agents that selectively bind to specific families of 5-HTreceptors with high affinity.

SUMMARY OF THE INVENTION

[0009] It is an object of this invention to provide compounds having theformula

[0010] In the compounds, R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl,alkylaryl, or substituted or unsubstituted branched or unbranched C₁-C₁₀alkyl or alkylaryl, and may be the same or different, and X may be a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, or c) a heteroatom or heteroatomic group selected from thegroup consisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be—H, —CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂) ₄CH₃, phenyl, or —OH. In someembodiments, R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be—CH₂—, —C(CH₃)₂—, —O— or —S—.

[0011] Specific embodiments include compounds with the followingformulas:

[0012] The invention further provides a pharmaceutical compositioncomprising, a compound of formula

[0013] in which R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl,alkylaryl, or substituted or unsubstituted branched or unbranched C₁-C₁₀alkyl or alkylaryl, and may be the same or different, and X may be a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, or c) a heteroatom or heteroatomic group selected from thegroup consisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be—H, —CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH_(3,) phenyl, or —OH. In someembodiments, R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be—CH₂—, —C(CH₃)₂—, —O— or —S—, and a pharmaceutically acceptable carrier.

[0014] The present invention also provides a method of treating acondition caused by abnormal serotonin activity in a patient in needthereof. The method includes the step of administering a compound offormula

[0015] in which R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl,alkylaryl, or substituted or unsubstituted branched or unbranched C₁-C₁₀alkyl or alkylaryl, and may be the same or different, and X may be a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, or c) a heteroatom or heteroatomic group selected from thegroup consisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be—H, —CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH_(3,) phenyl, or —OH. In someembodiments, R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be—CH₂—, —C(CH₃)₂—, —O— or —S—. The compound is administered in a quantitysufficient to ameliorate symptoms of said condition in said patient. Thecondition may be for example, clinical depression or anxiety,schizophrenia, schizoaffective disorder, and various eating and sleepingdisorders. The compound may be an antagonist of 5HT2 receptors, anantagonist of H1 receptors, or an antagonist of both 5HT2 receptors andH1 receptors.

[0016] The invention further provides a method of blocking a 5HT2receptor in a patient in need thereof. The method includes the step ofadministering to the patient of a compound of formula

[0017] in which R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl,alkylaryl, or substituted or unsubstituted branched or unbranched C₁-C₁₀alkyl or alkylaryl, and may be the same or different, and X may be a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, or c) a heteroatom or heteroatomic group selected from thegroup consisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be—H, —CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH_(3,) phenyl, or —OH. In someembodiments, R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be—CH₂—, —C(CH₃)₂—, —O— or —S—. The compound is administered in a quantitysufficient to block the 5HT2 receptor.

[0018] The invention further provides a method of blocking an H1receptor in a patient in need thereof The method includes the step ofadministering to the patient a compound of formula

[0019] in which R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl,alkylaryl, or substituted or unsubstituted branched or unbranched C₁-C₁₀alkyl or alkylaryl, and may be the same or different, and X may be a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, or c) a heteroatom or heteroatomic group selected from thegroup consisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be—H, —CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH_(3,) phenyl, or —OH. In someembodiments, R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be—CH₂—, —C(CH₃)₂—, —O— or —S—. The compound is administered in a quantitysufficient to block the H1 receptor.

[0020] The invention further provides a method of blocking both a 5HT2receptor and an H1 receptor in a patient in need thereof. The methodincludes the step of administering to the patient a compound of formula

[0021] in which R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl,alkylaryl, or substituted or unsubstituted branched or unbranched C₁-C₁₀alkyl or alkylaryl, and may be the same or different, and X may be a)carbon with two —H substituents, b) carbon with one or two lower alkylsubstituents, or c) a heteroatom or heteroatomic group selected from thegroup consisting of —O—; —S—; or —SO₂—. In some embodiments, R1 may be—H, —CH₂CH₂CH₂Ph, —OCH₃, —CH₂(CH₂)₄CH_(3,) phenyl, or —OH. In someembodiments, R2 may be —H, —CH₃ or CH₂Ph. In some embodiments, X may be—CH₂—, —C(CH₃)₂—, —O— or —S—. The compound is administered in a quantitysufficient to block both the 5HT2 and the H1 receptor.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

[0022] The present invention provides certain compounds that exhibithigh binding affinity for serotonin receptors 5-HT_(2A) and 5-HT_(2C).Without being bound by theory, the compounds appear to act asantagonists of these receptors. By “antagonist” we mean the compoundsblock the action of endogenous serotonin at the receptor and preventactivation of the receptor.

[0023] Further, the compounds of the present invention are highlyselective, being essentially devoid of affinity for the dopamine D2receptors and the serotonin and norepinephrine transporters. As such,the compounds are useful for treating conditions for which it isdesirable to selectively block serotonin receptor function with anantagonist. Because the compounds are highly selective for the targetreceptors, they cause fewer side effects than previously known serotoninreceptor ligands.

[0024] A generic chemical structure of the compounds of the presentinvention is given in Formula 2.

[0025] In Formula 2:

[0026] R1 and R2 may be —H, —OH, —OCH₃, halogen, aryl, alkylaryl, orsubstituted or unsubstituted branched or unbranched C₁-C₁₀ alkyl oralkylaryl, and may be the same or different. X may be a) carbon with two—H substituents, b) carbon with one or two lower alkyl substituents, orc) a heteroatom or heteroatomic group, examples of which include but arenot limited to —O—, —S—, and —SO₂—.

[0027] By “alkylaryl” we mean an aryl substituted with a C₁-C₄ alkyl, ora C₁-C₁₀ alkyl bridging between an aryl substituent (e.g. phenyl) andthe phenyl moiety depicted in Formula 2. “Phenyl” and “benzyl” are usedinterchangably herein. Lower alkyl substituents include branched orunbranched C₁-C₄ alkyl groups such as methyl, ethyl, etc. Branched orunbranched C₁-C₁₀ alkyl or alkylaryl may be substituted, i.e. one ormore of the hydrogens may be replaced with a non-hydrogen atom orchemical group, for example, with other alkyl groups such as loweralkyls, phenyl, etc.

[0028] Exemplary substituents R₁, R₂ and X of generic Formula 2 are asgiven in Table 1 where “Compound Number” refers to the number assignedto the compound in the synthesis schemes described in the Examplessection. TABLE 1 Examples of R₁, R₂ and X Substituents Compound NumberR₁ R₂ X  [5] —H —H —CH₂— [23] —CH₂CH₂CH₂Ph —H —CH₂— [17] —OCH₃ —H —CH₂—[21] —CH₂(CH₂)₄CH₃ —H —CH₂—  [17a] —OH —H —CH₂— [25] —Ph —H —CH₂—  [6]—H —CH₃ —CH₂—  [7] —H —CH₂Ph —CH₂— [22] —CH₂CH₂CH₂Ph —CH₂Ph —CH₂— [16]—OCH₃ —CH₂Ph —CH₂— [20] —CH₂(CH₂)₄CH₃ —CH₂Ph —CH₂— [18] —OH —CH₂Ph —CH₂—[12] —H —H —C(CH₃)₂— [30] —H —H —O— [36] —H —H —S—

[0029] The simplest “least substituted” compound of the presentinvention is spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5] (SPAN),the formula for which is given in Formula 3.

[0030] In compound [5], the synthesis of which is described in Example1, R₁ and R₂ are both —H and X is —CH₂—. The other compounds of theinvention are generally substituted with more complex chemical groups(i.e. with chemical groups composed of more atoms) and thus may beconsidered as derivatives or analogs of [5]. By “derivatives” or“analogs” we mean that the other compounds of the invention have thebasic chemical structure of compound [5] but contain different chemicalgroups at one or more of positions R₁, R₂ and X.

[0031] The compounds of the present invention are ligands of (i.e. bindto) serotonin receptors 5-HT₂ and 5-HT_(2A) and 5-HT_(2C). By “highaffinity” we mean that the compounds display a Ki in the range of aboutless than 1 to about 500 nM. In contrast, compounds with low or moderateaffinities diplay Ki values in the range of about 2000 to about 10,000nM, and about 500 to about 2000 nM, respectively. For example, compound[5] displays a Ki of 4nM for 5-HT₂ receptors and a Ki of 24 nM for thestructurally related 5-HT_(2c) receptor and is therefore a high affinityligand for both receptors.

[0032] In addition, the compounds of the present invention are selectivefor 5HT₂ serotonin receptors 5-HT₂, 5-HT_(2A) and 5-HT_(2C). By“selective” we mean that the affinity of the compounds for serotoninreceptors is significantly higher than for other related receptor types.For example, a compound with low selectivity typically has an affinityof about 10-fold or less higher than for other related receptor types,whereas moderately and highly selective compounds display about 10-100fold and about 100 to 10,000 fold higher affinities, respectively. By“related receptor types” we mean other receptors implicated in the mostserous side effects of typical 5HT₂ antagonists, e.g. the D2 receptor,and the serotonin and norepinephrine transporters. For example, compound[5] displays a Ki of 4 nM for the 5-HT₂ receptor and a Ki of 24 nM forthe structurally related 5-HT_(2c) receptor but is essentially devoid ofbinding activity for the dopamine D2 receptor (Ki=5040 nM), theserotonin transporter (Ki>10,000 nM) and the norepinephrine transporter(Ki>10,000 nM).

[0033] The compounds of the present invention are useful in treating avariety of disorders that result from abnormal serotonin activity. Theymay be used as prophylactic and/or acute-phase remedies for the reliefand reversal of serotonin-regulated symptoms. In particular, disordersthat result from an increased synaptic concentration of serotonin, inparticular as found in depressive disorders, and that can be amelioratedby inhibition of the 5HT₂ serotonin receptors. Examples of suchconditions include but are not limited to clinical depression oranxiety, schizophrenia, schizoaffective disorder, and various eating andsleeping disorders.

[0034] The present invention also encompasses a pharmaceuticalpreparation comprising at least one compound of the present inventiontogether with a pharmaceutically acceptable carrier. The compounds ofthe invention can be used either as the free base or as thepharmaceutically acceptable acid-addition salt form, for example,hydrochloride, hydrobromide, tartrate, and maleate. Such apharmaceutical preparation may be in any of many forms suitable foradministration of drugs, including but not limited to injectable dosageforms and solid dosage forms such as tablets, capsules, and the like.The compounds can be administered in the pure form or in apharmaceutically acceptable formulation including suitable elixirs,binders, and the like, or as pharmaceutically acceptable salts or otherderivatives. It should be understood that the pharmaceuticallyacceptable formulations and salts include liquid and solid materialsconventionally utilized to prepare injectable dosage forms and soliddosage forms such as tablets and capsules. Water may be used for thepreparation of injectable compositions which may also includeconventional buffers and agents to render the injectable compositionisotonic. Other potential additives include: colorants; surfactants(TWEEN, oleic acid, etc.); and binders or encapsulants (lactose,liposomes, etc). Solid diluents and excipients include lactose, starch,conventional disintergrating agents, coatings and the like.Preservatives such as methyl paraben or benzalkonium chloride may alsobe used. Depending on the formulation, it is expected that the activecomposition will consist of 1-99% of the composition and the vehicular“carrier” will constitute 1-99% of the composition. The pharmaceuticalcompositions of the present invention may include any suitablepharmaceutically acceptable additives or adjuncts to the extent thatthey do not hinder or interfere with the therapeutic effect desired ofagent.

[0035] The invention further provides a method for treating clinicaldisorders resulting from aberrant serotonin activity in a patient inneed of such treatment. According to the method, at least one compoundof the present invention is administered to the patient in a quantitysufficient to ameliorate symptoms of such disorders.

[0036] Those of skill in the art will recognize that the exact dosage ofan agent to be so-administered may vary depending on factors such as theage, gender, weight and overall health status of the individual patient,as well as on the nature of the disorder being treated. Generally,dosages in the range of from about 0.1 to about 1000 mg active agent/kgbody weight/24 hr., and more preferably about 1.0 to about 500.0 mgactive agent/kg body weight/24 hr., and even more preferably about 10 toabout 100.0 mg active agent/kg body weight/24 hr., are effective. Thelevel of efficacy and optimal amount of dosage for any given compoundmay vary from compound to compound.

[0037] The agents of the present invention may be administered by any ofa wide variety of means which are well known to those of skill in theart, (including but not limited to intravenously, intramuscularly,intraperitoneallly, orally, rectally, intraocularly, and the like) or byother routes (e.g. transdermal, sublingual, aerosol, etc.). and may bein any form (e.g. liquid, solid, etc.) which is suitable for the meansof administration. Further, the agents may be administered either aloneor together with other medications in a treatment protocol.

[0038] Further, several of the compounds (e.g. [5], [16], [17], [30] and[36] of the present invention also display a high affinity for thehistamine H1 receptor, high affinity being defined herein as displayinga Ki value of about 100 nm or less. This receptor is known to functionin allergic reactions in the periphery and regulation of sleep in thecentral nervous system. Thus, compounds of the present invention mayalso be utilized to treat conditions in which it is desirable toantagonize the action of histamine at Hi receptors. Examples of suchconditions include but are not limited to sleep disorders and allergicreactions.

[0039] Finally, the compounds of the present invention may be used asabove for determining 5-HT₂ receptor family function, for example, in alaboratory or clinical diagnostic setting.

EXAMPLES Example 1

[0040] Synthesis of Spiro[9,10-dihydroanthracene-]9,3′-pyrrolidine [5](SPAN)

[0041] The synthesis of SPAN was carried out as depicted in Scheme 1 andas further described below. Referring to Scheme 1, reagents andconditions were as follows: (a) POCl₃, reflux, 45 min, (b) C₂H₅ONa,BrCH₂COOC₂H₅, EtOH, reflux, (c) 10% Pd/C, CH₃OH, HCl, (d)Borane-THF/THF; 6.0M HCl.

[0042] 9-Cyano-9,10-dihydroanthracene [2]

[0043] POCl₃ (5.5 mL, 59 mmol) was added to crystalline9,10-dihydroanthracene carboxamide [1] (0.54 g, 2.43 mmol) whilestirring. The solution was then heated at reflux (45 min), when TLCshowed complete absence of starting material. The solution was thenpoured into a mixture of crushed ice and NH₄OH with vigorous stirring.The solution was stirred (15 min) and excess of NH₄OH was added to keepthe solution alkaline. The solid formed was extracted with ether (3×50ml). The combined ether extracts were washed with water and brine, dried(MgSO₄) and evaporated under reduced pressure to give an yellow oilwhich crystallized immediately. The product was purified by mplc usingpet. ether: acetone (9:1) as eluent to give 0.296 g (60%) of pure9-Cyano-9,10-dihydroanthracene as colorless crystals mp. 106-108° C.**lit. mp. 101-102° C. IC^(cm−1) 2215. ¹H NMR (CDCl₃)d: 3.87-3.93 (d,J=18 Hz, 1H, CH₂), 4.05-4.11 (d,J=18 Hz, 1H, CH₂), 5.02 (s, 1H, CH),7.28-7.79 (m, 8H, Ar—H). ¹³C NMR (CDCl₃) d: 36.14, 37.60, 119.54,125.88, 127.12, 127.60, 128.53, 128.82, 129.56, 131.34, 136.65

[0044] (9-Cyano-9,10-dihydro-anthracen-9-yl)-acetic acid ethyl ester [3]

[0045] 9-Cyano-9,10-dihydroanthracene [2] (1.25 g, 6.09 mmol) was addedto sodium ethoxide prepared from Na (0.196 g, 8.53 mmol) and EtOH (10mL) and heated at reflux (1 hr). The solution was then cooled in an icebath and ethyl bromoacetate (1.42 g, 8.53 mmol) was added drop wise viaa syringe. The resulting mixture was heated at reflux (4 h) cooled andfiltered. The residue was washed with ether (25 mL). Water (25 mL) wasadded to the filterate and the organic layer was separated. The aqueouslayer was once again extracted with ether (25 mL). The combined etherextracts were washed with water and brine, dried (MgSO₄) and evaporatedunder reduced pressure to give an oil which was purified by mplc usingpet. ether: EtOAc (9:1) as eluent to give 1.245 g (70%) of the productas a colorless oil, which crystallized on prolonged standing: mp 69-70°C. (EtOAc-pet. ether).¹H NMR (CDCl₃)d: 1.10-1.15 (t, J=7.5 Hz, CH₃),2.85 (s, 2H, CH₂), 3.97-4.14 (m, 4H, CH₂), 7.33-7.89 (m, 8H, Ar—H). ¹³CNMR (CDCl₃) d: 14.53, 35.27, 46.05, 46.28, 61.63, 121.89, 127.58,127.70, 128.93, 134.21, 135.10, 167.96

[0046] Spiro [9,10-dihydroanthracene]-9,4′-pyrrolidin-2′-one [4]

[0047] A mixture of (9-Cyano-9,10-dihydro-anthracen-9-yl)-acetic acidethyl ester [3] (0.60 g, 2.061 mol), 10% Pd/C (0.15 g) in methanol (40mL) and HCl (1 mL) was hydrogenated at 50 kg/cm³ (3 days). The catalystwas filtered off with celite and the solvent was evaporated underreduced pressure to give a white semisolid. Water (25 mL) was added andthe solution was made basic with 10% NaOH and extracted with EtOAc (3×25mL). The combined EtOAc extracts were washed with water and brine, dried(MgSO₄) and evaporated under reduced pressure to give a colorless oilwhich crystallized immediately on standing. The solid was recrystallizedfrom CHCl₃-pet.ether to give 0.35 g (68%) of the pure amide as a whitecrystalline solid: mp 189-190° C. ¹H NMR (CDCl₃)d: 3.06 (s, 2H, CH₂),3.70 (s, 2H, CH₂), 4.00-4.06 (d, J=18 Hz, 1H, CH₂), 4.09-4.15 (d, J=18Hz, 1H, CH₂), 6.15 (s, 1H, NH), 7.24-7.58 (m, 8H, Ar—H). ¹³C NMR (CDCl₃)d: 36.37, 43.20, 47.49, 55.66, 125.04, 127.50, 128.73, 136.35, 141.36,178.40

[0048] Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5]

[0049] A 1.0 M solution of BH₃-THF complex (7.00 ml, 7.00 mmol) wasadded at 0° C. to a well stirred solution of4-Spiro-9-(9,10-dihydroanthracene)pyrrolidin-2-one [4](0.35 g, 1.40mmol) in anhydrous THF (2 mL). The solution was brought to RT and thenheated at reflux (8 h), cooled to RT and 6 M solution of HCl (4 mL) wasadded cautiously to the reaction mixture. The reaction mixture was thenheated at reflux (1 hr), cooled to RT and the solvent was removed underreduced pressure, resulting in a white suspension. Water (20 mL) wasadded to it and extracted with EtOAc (20 mL). The aqueous phase was thenbasified using 10% NaOH and extracted with Et₂O (3×25 ml). The combinedEt₂O extracts were washed with water and brine, dried (MgSO₄) and thesolvent was removed under reduced pressure to give 0.31 g (94%) theamine as colorless oil. The oil started to darken rapidly and wasdissolved in anhydrous acetone and fumaric acid (0.15 g, 1.31 mmol) wasadded and heated. The solution on cooling gave the fumarate as pale pinkpowder, which remained on two recrystallizations. mp. 190.5-191.5° C.(EtOAc-CH₃OH). ¹H NMR (DMSO-d₆)d: 2.25-2.30 (t, J=7.5 Hz, 2H, CH₂),3.21-3.26 (t, J=7.5 Hz, 2H, CH₂), 3.55 (s, 2H, CH₂), 4.06 (s, 2H, CH₂),6.44 (s, 1H, fumarate), 7.20-7.56 (m, 8H, Ar—H). ³C NMR (DMSO-d₆) d:36.22, 36.67, 45.18, 51.09, 54.10, 124.43, 126.69, 126.76, 128.17,135.84, 137.08, 141.44, 168.96. Anal. Calcd. For (C₁₇H₁₇N.½C₄H₄O₄): C,77.79; H, 6.52; N, 4.77. Found. C, 77.12; H, 6.56; N, 4.78

Example 2

[0050] Synthesis ofSpiro[9,10-dihydroanthracene]-9,3′-(1-methyl)-pyrrolidine [6]

[0051] The synthesis of compound [6] was carried out as depicted inScheme 2 and as described below. Referring to Scheme 2, reagents andconditions were as follows: (a) NaCNBH₃/CH₃CN.

[0052] Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5] (0.23 g, 1.0mmol) was dissolved in a mixture of anhydrous CH₃CN (10 mL) andformaldehyde (37%, 0.5 mL). NaCNBH₃ (0.10 g, 1.6 mmol) was added inportions over 5 min. and the reaction mixture was stirred (45 min) atroom temperature. Glacial acetic acid was added dropwise until thesolution tested neutral. Stirring was continued for another 45 min,glacial acetic acid being added occasionally to maintain pH. The solventwas removed under reduced pressure and 2 N NaOH (20 mL) was added andextracted with Et₂O (2×25 mL). The combined Et₂O extracts were thenextracted with 1N HCl (3×25 mL). The acid extracts were combined andneutralized with solid NaOH and extracted with Et₂O (3×25 mL). Thecombined Et₂O extracts were washed with water, brine, dried (MgSO₄) andevaporated under reduced pressure to give 0.155 g (63%) of colorlessoil. The oil was dissolved in anhydrous acetone and fumaric acid (0.079g, 0.68 mmol) was added and heated to dissolve the acid. The solution oncooling the product as a white powder: mp. 162-163° C. (EtOAc-CH₃OH). ¹HNMR (DMSO-d₆)δ: 2.39-2.44 (t, J=7.5 Hz, 2H, CH₂), 2.46 (s, 3H, CH₃),3.00-3.04 (t, J=6 Hz, 2H, CH₂), 3.11 (s, 2H, CH₂), 4.02 (s, 2H, CH₂),6.59 (s, 1H, fumarate), 7.18-7.62 (m, 8H, Ar—H). ¹³C NMR (DMSO-d₆) δ:35.77, 38.50, 42.20, 49.94, 55.85, 67.28, 125.43, 126.39, 126.56,127.89, 134.56, 136.19, 143.03, 166.67. Anal. Calcd. For(C₁₈H₁₉N.C₄H₄O₄.0.25 H₂O): C, 71.42; H, 6.40; N, 3.78. Found. C, 71.68;H, 6.68; N, 3.75

Example 3

[0053] Synthesis ofSpiro[9,10-dihydroanthracene]-9,3′-(1-benzyl)-pyrrolidine [7]

[0054] The synthesis of compound [7] was from [5] was carried out asdepicted in Scheme 3 and as described below. Regarding Scheme 3,reagents and conditions were as follows: C₆H₅CH₂Br, Et₃N, CH₂Cl₂,reflux.

[0055] Spiro[9,10-dihydroanthracene]-9,3′-pyrrolidine [5] (0.125 g, 0.53mmol) was dissolved in anhydrous CH₂Cl₂ ( 10 mL) and triethylamine wasadded dropwise. The reaction mixture was cooled in an ice-bath andbenzyl bromide (0.113 g, 0.66 mmol) in anhydrous CH₂Cl₂ (5 mL) was addedvia syringe. The reaction mixture was warmed to room temperature andthen heated at reflux (4 h). The solvent was removed under reducedpressure and water (20 mL) was added to the residue and extracted withEtOAc (3×25 mL). The combined EtOAc extracts were washed with water,brine, dried (MgSO₄) and evaporated under reduced pressure to give adark brown oil which was purified by mplc using CH₂Cl₂ as eluent to give0.12 g (70%) of the amine as a colorless oil. The oil was dissolved inanhydrous acetone and fumaric acid (0.047 g, 0.40 mmol) was added andheated to dissolve the acid. The solution on cooling gave the product asa white powder: mp. 175-176° C. (EtOAc-CH₃OH). ¹H NMR (DMSO-d₆)δ:2.31-2.35 (t, J=6 Hz, 2H, CH₂), 2.87-2.92 (t, J=7.5 Hz, 2H, CH₂), 3.02(s, 2H, CH₂), 3.74 (s, 2H, CH₂), 3.98 (s, 2H, CH₂), 6.61 (s, 1H,fumarate), 7.14-7.66 (m, 8H, Ar—H). ¹³C NMR (DMSO-d₆) δ: 35.56, 49.22,53.81, 59.68, 66.15, 125.67, 126.19, 126.53, 127.28, 127.78, 128.60,128.81, 134.40, 135.83, 143.92, 166.39. Anal. Calcd. For(C₂₄H₂₃N.C₄H₄O₄): C, 76.16; H, 6.16; N, 3.17. Found. C, 76.08; H, 6.25;N, 3.21

Example 4

[0056] Synthesis ofSpiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,3′-pyrrolidine [12]

[0057] Compound 12 was synthesized as depicted in Scheme 4 and asdescribed below. Referring to Scheme 4, reagents and conditions were asfollows: (a) POCl₃, reflux, 45 min, (b) C₂H₅ONa, BrCH₂COOC₂H₅, EtOH,reflux, (c) 10% Pd/C, CH₃OH, HCl, (d) Borane-THF/THF; 6.0M HCl.

[0058] 9-cyano-10,10-Dimethyl-9,10-dihydroanthracene [9]

[0059] POCl₃ (25 mL, 00 mmol) was added to crystalline10,10-Dimethyl-9,10-dihydroanthracene-9-carboxamide [8] (1.25 g, 4.9mmol) while stirring. The solution was then heated at reflux (30 min),when TLC showed complete absence of starting material. The solution wasthen poured into a mixture of crushed ice and NH₄OH with vigorousstirring. The solution was stirred for 15 minutes and excess of NH₄OHwas added to keep the solution alkaline. A solid substance separated outwhich was extracted with ether (3×50 ml). The combined ether extractswere washed with water, brine, dried (MgSO₄) and evaporated underreduced pressure to give an light yellow oil which crystallizedimmediately. The product obtained was chromatographically pure andrecrystallized readily from EtOH to give 1.0 g (86%) of the product ascolorless prisms. mp. 91-92° C. ¹H NMR (CDCl₃)d: 1.54 (s, 3H, CH₃), 1.79(s, 3H, CH₃), 5.32 (s, 1H, CH), 7.32-7.68 (m, 8H, Ar—H). ¹³C NMR (CDCl₃)d: 30.22, 30.33, 36.95, 125.77, 127.43, 127.92, 129.28. Anal. Calcd. For(C₁₇H₁₅N): C, H, N.

[0060] (9-Cyano-10,10-dimethyl-9,10-dihydro-anthracen-9-yl)-acetic acidethyl ester [10]

[0061] 9-cyano-10,10-Dimethyl-9,10-dihydroanthracene [9] (0.8 g, 3.42mmol) was added to sodium ethoxide prepared from Na metal (0.110 g, 4.80mmol) and ethanol (10 mL) and heated under reflux for one hour leadingto the development of a greenish brown solution. The solution was thencooled in an ice bath and ethyl bromoacetate (0.80 g, 4.80 mmol) wasadded dropwise via a syringe. The resulting mixture was then heated atreflux (4 h) and filtered. The solid residue was washed with ether (25mL). Water (25 mL) was added to the filterate and the organic layer wasseparated. The aqueous layer was once again extracted with ether (25mL). The combined ether extracts were washed with water, brine, dried(MgSO₄) and evaporated under reduced pressure to give an oil which waspurified by medium pressure liquid chromatography using pet. ether:EtOAc (9:1) as eluent to give 0.978 g (74%) of the product as acolorless oil. ¹H NMR (CDCl₃)d: 0.98-1.06 (t, 3H, CH₃), 1.64-1.67 (d,J=9Hz, 3H, CH₃), 1.71-1.74 (d, J=9 Hz, 3H, CH₃), 3.04-3.07 (d, J=9Hz,2H, CH₂), 3.86-3.94 (q, 2H, CH₂), 7.29-7.77 (m, 8H, Ar—H). ¹³C NMR(CDCl₃) d: 14.39, 33.85, 35.21, 38.37, 52.29, 61.38, 123.17, 127.53,127.84, 128.17, 129.48, 130.97, 143.23, 167.97.

[0062]Spiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,4′-pyrrolidin-2′-one[11]

[0063] A mixture of(9-Cyano-10,10-dimethyl-9,10-dihydro-anthracen-9-yl)-acetic acid ethyl ester [10](0.975 g, 3.05 mol), 10% Pd/C (0.1 g) in methanol (20 mL) and HCl (1 mL)was hydrogenat at 50 kg/cm³ (24 h). The catalyst was filtered off withcelite and the solvent was evaporated under reduced pressure to give awhite semisolid. Water (25 mL) was added and the solution was made basicwith 10% NaOH and extracted with EtOAc (3×25 mL). The combined EtOAcextracts were washed with water, brine and dried using anhydrous MgSO₄and evaporated under reduced pressure to give a colorless oil which waspurified by mplc using pet.ether: EtOAc (8:2) as eluent to give a whitesolid. The solid was recrystallized from CHCl₃-pet.ether to give 0.4 g(40%) ofthe pure amide as colorless needles. mp 236-237° C. ¹H NMR(CDC1₃)d: 1.68 (s, 6H, CH3), 3.07 (s, 2H, CH₂), 3.97 (s, 2H, CH₂),7.32-7.56 (m, 8H, Ar—H).¹³C NMR (CDCl₃) d: 35.17, 35.26, 37.89, 43.67,53.34, 63.86, 126.68, 126.98, 127.70, 128.00, 141.14, 142.47, 178.04

[0064] Spiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,3′-pyrrolidine[12]

[0065] A 1.0M solution of BH₃-THF complex (7.00 ml, 7.00 mmol) was addedat 0° C. to a well stirred solution ofSpiro[-(10,10-dimethyl)-9,10-dihydroanthracene]-9,4′-pyrrolidin-2′-one[11] (0.15 g, 0.54 mmol) in anhydrous THF (2 mL). The solution wasbrought to room temperature and then heated at reflux (8 h), cooled and6 M solution of HCl (4 mL) was added cautiously to the reaction mixture.The reaction mixture was then heated at reflux for an additional hour,cooled and the solvent was removed under reduced pressure, resulting ina white suspension. Water (20 mL) was added to it and extracted withEtOAc (20 mL). The aqueous phase was then basified using 10% NaOH andthe resultant solution was extracted with Et₂O (3×25 ml). The combinedEt₂O extracts were washed with water, brine, dried (MgSO₄) and thesolvent was removed under reduced pressure to give 0.129 g (90%) theamine as a colorless oil. The oil was dissolved in anhydrous acetone andfumaric acid (0.062 g, 0.538 mmol) was added and heated. The solution oncooling gave the fumarate as a white powder: mp. 207-208° C.(EtOAc-CH₃OH). ¹H NMR (DMSO-d₆)d: 1.57 (s, 3H, CH₃), 1.63 (s, 3H, CH₃),2.31-2.36 (t, J=7.5 Hz, 2H, CH₂), 3.51-3.56 (t, J=7.5 Hz, 2H, CH₂), 3.63(s, 2H, CH₂), 6.53 (s, 1H, fumarate), 7.27-7.64 (m, 8H, Ar—H). ¹³C NMR(DMSO-d₆) δ: 33.77, 35.19, 37.67, 47.00, 48.70, 48.88, 63.75, 126.70,127.17, 135.39, 140.55, 142.59, 168.28. Anal. Calcd. For(C₁₉H₂₁N.C₄H₄O₄): C, 72.80; H, 6.64; N, 3.69. Found C, 72.40, 6.64, 3.65

Example 5

[0066] Synthesis ofSpiro[-(3-methoxy)-9,10-dihydroanthracene]-9,3′-pyrrolidine [17]

[0067] The compound [17] was synthesized as depicted in Scheme 5 anddescribed below. Referring to Scheme 5, reagents and conditions were asfollows: (a) 2-Bromobenzaldehyde, anhydrous THF, 0° C. (b) LiAlH₄/AlCl₃,anhydrous Et₂O, reflux (c) n-BuLi, anhydrous Et₂O,n-benzyl-3-pyrrolidone (d) CH₃SO₃H, rt (e) 10% Pd/C, CH₃OH.

[0068] (2-Bromo-phenyl)-(3-methoxy-phenyl)-methanol [13]

[0069] 3-Methoxyphenyl magnesium bromide (1.0 M solution in THF; 5.4 mL,5.4 mmol) was taken in a flask under N₂ and cooled (0° C.).2-Bromobenzaldehyde (1 g, 5.4 mmol) in anhydrous THF (10 mL) was addeddropwise via syringe over 5 min. The reaction mixture was stirred atthis temperature for 20 min. and slowly brought to room temperature.After stirring for another 30 min. satd. NH₄Cl solution (20 mL) wasadded and the mixture was extracted with Et₂O (3×25 mL). The combinedEt₂O extracts were washed with water, brine, dried (MgSO₄) andevaporated under reduced pressure to give a yellow oil. The oil waspurified by mplc using CH₂Cl₂ as eluent to give 1.275 g (81%) of thealcohol as a colorless oil. ¹H NMR (CDCl₃)d: 2.71 (s, 1H, OH), 3.78 (s,3H, CH₃), 6.15 (s, 1H, CH), 6.80-7.58 (m, 8H, Ar—H). ³C NMR (CDCl₃) d:55.80, 75.16, 113.29, 119.90, 123.39, 128.33, 129.11, 129.71, 130.08,133.39.

[0070] 3-(2-Bromobenzyl)-methoxy benzene [14]

[0071] LiAlH₄ (0.154 g, 4.06 mmol) was suspended in anhydrous Et₂O (10mL) under a N₂ atmosphere and cooled (0° C.) with stirring. AnhydrousAlCl₃ (1.08 g, 8.14 mmol)was dissolved in ice-cold anhydrous Et₂O (20mL) and added dropwise to the LiAlH₄ suspension. After complete additionthe suspension was stirred at the same temperature (20 min.).(2-Bromo-phenyl)-(3-methoxy-phenyl)-methanol [13] (0.68 g, 2.32 mmol)was dissolved in anhydrous Et₂O (10 mL) and added dropwise via syringeto the suspension. After complete addition the reaction mixture washeated at reflux (4 h), cooled (0° C.) and EtOAc was added dropwise todestroy the excess of the reagent and the mixture was added to 20% aq.H₂SO₄ (50 mL). Et₂O (50 mL) was added and extracted. The Et₂O layer wasseparated, washed with water, brine, dried (MgSO₄) and evaporated togive a reddish yellow oil. The oil was purified by mplc using pet.ether-CH₂Cl₂ (9:1) as eluent to give 0.485 g (75%) of the pure productas a colorless oil. ¹H NMR (CDCl₃)d: 3.81 (s, 3H, CH₃), 4.14 (s, 2H,CH₂), 6.79-7.62 (m, 8H, Ar—H). ¹³C NMR (CDCl₃) d: 42.34, 55.69, 112.07,122.02, 125.48, 128.07, 128.50, 130.02, 131.66, 133.43.

[0072]1-Benzyl-3-[2-(3-methoxy-benzyl)-phenyl]-pyrrolidin-3-ol [15]

[0073] 3-(2-Bromobenzyl)-methoxy benzene (0.5 g, 1.80 mmol) [14] wasdissolved in anhydrous Et₂O (15 mL)and cooled to −78° C. under N₂.n-butyl lithium (0.8 mL, 1.98 mmol, 2.5M soln. in Et₂O) was addeddropwise over 5 min. and stirred for 30 min. The reaction mixture wasthen brought to room temperature over 1 hr. The reaction mixture wascooled to −78° C. and n-benzyl-3-pyrrolidone (0.31 mL, 1.9 mmol) inanhydrous Et₂O (5 mL) was added via syringe with stirring. The reactionmixture was brought to room temperature over 3 hr. Water (50 mL) wasadded and the organic phase was extracted. The aqueous phase wasextracted with Et₂O (50 mL) and the combined Et₂O extracts were washedwith water, brine and dried (MgSO₄). Et₂O was removed under reducedpressure to give a red oil which was purified by mplc usingCH₂Cl₂:(CH₃)₂CO (9:1) as eluent to give 0.3 g (45%) of the aminoalcoholas a dark yellow oil. A small sample was converted into its filmarate,mp 148-149° C. (EtOAc-CH₃OH). ¹H NMR (DMSO-d₆)d: 2.11-2.40 (m, 2H, CH₂),2.96-2.99 (d, 4H, CH₂), 3.23-3.27 (d, 1H, OH), 3.67 (s, 3H, CH₃), 3.89(s, 2H, CH₂), 4.27 (s, 2H, CH₂), 6.58-7.42 (m, 14H, Ar—H). ¹³C NMR(CDCl₃) d: 38.21, 52.70, 55.21, 59.71, 66.46, 80.27, 111.23, 115.17,121.54, 125.84, 125.97, 127.38, 127.86, 128.67, 129.38, 129.58, 132.17,134.71, 139.49, 143.93, 159.37, 160.97.

[0074]3-Methoxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[16]

[0075] Methanesulfonic acid (5 mL) was added to1-Benzyl-3-[2-(3-methoxy-benzyl)-phenyl]-pyrrolidin-3-ol [15] (0.5 g,1.33 mmol) taken in a round bottom flask equipped with a stirrer underN₂ at room temperature. Stirring was continued (30 min.), when TLCshowed absence of starting material. Crushed ice/water was added to thereaction mixture and the solution was made basic by the addition of 10%NaOH. The alkaline reaction mixture was extracted with EtOAc (3×25 mL).The combined EtOAc extracts were washed with water, brine and dried(MgSO₄). EtOAc was removed under reduced pressure to give a red oilwhich was purified by mplc using CH₂Cl₂:(CH₃)₂CO (9:1) as eluent to give0.24 g (52%) of the amine as a colorless oil. The oil was converted intoits oxalate salt mp. 187-188° C. (Acetone). Anal. Calcd. For(C₂₅H₂₅NO.C₂H₂O₄): C, 72.79; H, 6.10; N, 3.14. Found. C, 72.75; H, 6.15;N, 3.11. ¹H NMR (DMSO-d₆)d: 2.52 (s, 2H, CH₂), 3.27 (bs, 2H, CH₂), 3.40(s, 2H, CH₂), 3.77 (s, 3H, CH₃), 4.00 (s, 2H, CH₂), 4.13 (s, 2H, CH₂)6.82-7.63 (m, 12H, Ar—H). ¹³C NMR (DMSO-d₆) d: 35.60, 48.56, 52.92,54.98, 58.54, 111.67, 112.74, 124.45, 125.75, 126.18, 127.59, 128.08,128.42, 129.57, 135.96, 137.52, 155.71, 157.52, 162.69.

[0076] 3-Methoxy-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydro-anthracene[17]

[0077]3-Methoxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[16] (0.23 g, 0.647 mmol) was dissolved in CH₃OH (15 mL) and 10% Pd/C(0.050 g) was added under N₂. A few drops of HCl were added and thereaction mixture was hydrogenated on a parr-hydrogenator at 50 psiovernight and the catalyst was filtered off using celite. The filteratewas evaporated and water (15 mL) was added and basified using 10% NaOH.The basic solution was extracted with CH₂Cl₂ (2×25 mL) and the combinedextracts were washed with water, brine and dried (MgSO₄). The CH₂Cl₂ wasremoved under reduced pressure to give a yellow oil which was purifiedby mplc using CH₂Cl₂:CH₃OH (9:1) as eluent to give 0.126 g (74%) of theproduct as a colorless oil which darkened rapidly. The oil was convertedinto its oxalate salt, mp. 99-101° C. (Acetone). Anal. Calcd. For(C₁₈H₁₉NO.C₂H₂O₄.0.5(CH₃)₂CO. 0.5 H₂O) : C, 65.63; H, 6.40; N, 3.56.Found. C, 65.39; H, 5.99; N, 3.31. ¹H NMR (CDCl₃)d: 2.32-2.38 (m, 2H,CH₂), 2.97-3.02 (t, J=15 Hz, 2H, CH₂), 3.18 (bs 2H, CH₂), 3.83 (s, 3H,CH₃), 4.05 (bs, 2H, CH₂), 6.79-7.77 (m, 7H, Ar—H). ¹³C NMR (CDCl₃) d:36.75, 41.94, 52.78, 55.27, 65.73, 112.93, 125.87, 126.24, 126.90,127.47, 128.01, 128.80, 129.61.

Example 6

[0078] Synthesis of3-Hydroxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10- dihydroanthracene[18]

[0079] Compound 18 was synthesized as depicted in Scheme 6 and describedbelow. Referring to Scheme 6, reagents and conditions were as follows:BBr₃, CH₂Cl₂, −78° C.

[0080] To a solution of3-Methoxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[16] (0.24 g, 0.675 mmol) in anhydrous CH₂Cl₂ (10 mL) at −78° C. wasadded BBr₃ (2.70 mL, 2.7 mmol, 1M soln. in CH₂Cl₂) dropwise. Thetemperature was raised to ambient temperature over a period of 2 hr. andstirring was continued for 6 hr. The reaction mixture was cooled to −78°C. and CH₃OH (5 mL) was added dropwise via syringe and the solvent wasremoved under reduced pressure. The residue was redissolved in CH₃OH andsatd. Solution of NaHCO₃ was added and extracted with Et₂O (2×25 mL).The combined Et₂O extracts were washed with water, brine and dried(MgSO₄). The solvent was removed under reduced pressure to give a darkyellow oil. The oil was purified by mplc using CH₂Cl₂:(CH₃)₂CO (9:1) aseluent to give 0.21 g (91%) the product as a pale yellow oil. The oilwas converted into its oxalate salt mp. 133-134° C. (EtOAC—CH₃OH). Anal.Calcd. For (C₂₄H₂₃NO.C₂H₂O₄. 0.5H₂O): C, 70.89; H, 5.94; N, 3.17. Found.C, 70.90; H, 5.88; N, 3.30. ¹H NMR (DMSO-d₆)d: 2.50 (bs, 2H, CH₂), 3.30(bs, 2H, CH₂), 3.42 (bs, 2H, CH₂), 3.91 (bs, 2H, CH₂), 4.17 (bs, 2H,CH₂), 6.65-7.57 (m, Ar—H, 12H). ¹³C NMR (DMSO-d₆) d: 36.41, 49.40,53.69, 59.25, 64.40, 113.81, 115.09, 127.08, 129.34, 130.77, 132.40,137.05, 138.24, 142.73, 156.49, 164.15, 208.92.

Example 7

[0081] Synthesis ofSpiro[-(3-hydroxy)-9,10-dihydroanthracene]-9,3′-pyrrolidine [19]

[0082] Compound [19] was synthesized as depicted in Scheme 7 anddescribed below. Referring to Scheme 7, reagents and conditions were asfollows: BBr₃, CH₂Cl₂, −78° C.

[0083] Spiro[-(3-methoxy)-9,10-dihydroanthracene]-9,3′-pyrrolidine [17](0.2 g, 0.756 mmol) was dissolved in anhydrous CH₂Cl₂ ( 10 mL) andcooled to −78° C. under N₂. BBr₃ (3.78 mL, 1.0M soln. in CH₂Cl₂) wasadded dropwise via syringe over 15 min. The reaction mixture was allowedto stir at room temperature overnight and cooled to −78° C. AnhydrousCH₃OH (5 mL)was added dropwise and the solvents were evaporated underreduced pressure to give a dry solid. The solid was redissolved inanhydrous CH₃OH (5 mL) and EtOAc (35 mL) was added and cooled. Theproduct crystallized as a pale white solid, which was once againrecrystallized from EtOAc-CH₃OH to give 0.15 g (60%) ofthe product asits hydrobromide, mp. 150-151° C. (dec.). ¹H NMR (DMSO-d₆)d: 2.32-2.36(t, J=6 Hz, 2H, CH₂), 3.39 (bs, 2H, CH₂), 3.71 (bs, 2H, CH₂), 3.99 (bs,2H, CH₂), 6.65-7.54 (m, 7H, Ar—H), 9.28 (bs, 1H). ¹³C NMR (DMSO-d₆) d:35.86, 44.43, 49.37, 51.93, 112.80, 114.76, 124.76, 126.24, 126.74,127.98, 129.50, 137.06, 138.30, 139.80, 156.04, 195.17. Anal. Calcd. For(C₁₇H₁₇NO.HBr.0.5H₂O): C, 59.83; H, 5.61; N, 4.10. Found. C, 59.35; H,5.48; N, 3.60.

Example 8

[0084] Synthesis of3-n-Hexyl-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [21]

[0085] Compound [21] was synthesized as depicted in Scheme 8 and asdescribed below. Referring to Scheme 8, reagents and conditions were asfollows: (a) Triflic anhydride, C₅H₅N (b) 1-hexene, 9-BBN, PdCl₂(dppf),K₃PO₄, anhyd. THF (c) 10% Pd/C, CH₃OH, HCl.

[0086] 3-Trifluoromethane sulfonyloxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19]

[0087] To a solution of3-Hydroxy-9,9-[spiro-3′-(-benzyl)-pyrrolidinyl]-9,10-dihydro-anthracene[16] (0.765 g, 2.241 mmol) in pyridine (5 mL) at 0° C. was added triflicanhydride (0.961 g. 0.58 mL, 3.4 mmol) dropwise via syringe under N₂.The reaction mixture was gradually brought to room temperature andstirred (3 hr.). Crushed ice/water was added and the solution wasextracted with Et₂O (2×25 mL). The combined Et₂O extracts were washedwith water, brine, dried (MgSO₄) and evaporated under reduced pressureto give a red oil. The oil was purified by mplc using pet. Ether:acetone(9:1) as eluent giving 0.93 g (85%) of the triflate as a reddish brownoil. ¹H NMR (CDCl₃)d: 2.34-2.40 (m, 2H, CH₂), 2.85-2.88 (m, 2H, CH₂),2.99-3.15 (m, 2H, CH₂), 3.76 (s, 2H, CH₂), 4.02-4.05 (m, 2H, CH₂),7.13-7.84 (m, 12H, Ar—H). ¹³C NMR (CDCl₃) d: 35.43, 48.73, 53.95, 59.92,66.59, 118.58, 121.77, 126.54, 128.31, 133.85, 137.46, 142.69, 144.88,147.18

[0088]3-n-Hexyl-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[20]

[0089] An oven dried flask equipped with a septum inlet and condenserwas flushed with N₂ and charged with a soln. of 9-BBN (2.15 mL, 1.079mmol, 0.5 M soln.), cooled to 0° C. and 1-hexene (0.133 mL, 1.079 mmol)was added via syringe. The mixture was brought to room temperature andstirred (8 hr.). To the prepared BBN soln. was added K₃PO₄(0.312 g,1.471 mmol), PdCl₂(dppf) (0.020 g, 5 mol %) and 3-Trifluoromethanesulfonyloxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19](0.48 g, 0.980 mmol) in anhydrous THF (10 mL). The reaction mixture washeated at reflux overnight, cooled and water (20 mL) was added. Thereaction mixture was then extracted with EtOAc (3×25 mL). The combinedEtOAc extracts were washed with water, brine and dried (MgSO₄). Thesolvent was removed under reduced pressure to give a dark brown oil,which was purified by mplc using pet. Ether-EtOAc (9:1) as eluent togive 0.34 g (85%) of the product as an yellow oil. The oil was convertedinto its oxalate, mp. 135-136° C. (EtOAc-CH₃OH). ¹H NMR (CDCl₃)d:0.872.34-2.40 (bm, 13H, CH₂), 2.30-2.42 (bm, 2H, CH₂), 2.62 (bs, 2H,CH₂), 2.93 (bs, 2H, CH₂), 3.13 (bs, 2H, CH₂), 3.75 (bs, 2H, CH₂), 4.00(bs, 2H, CH₂), 7.04-7.72 (m, 12H, Ar—H). ¹³C NMR (CDCl₃) d: 27.19,28.87, 35.62, 35.77, 41.37, 48.69, 54.26, 60.14, 67.07, 111.26, 123.54,125.55, 126.06, 126.58, 127.24, 128.02, 128.37, 134.70, 134.77, 135.04,139.33, 139.55, 140.14, 140.32, 142.28, 144.18. Anal. Calcd. For(C₃₀H₃₅N. C₂H₂O₄.0.5H₂O) : C, 75.56; H, 6.52; N, 2.75. Found. C, 75.04;H, 6.76; N, 2.91.

[0090] 3-n-Hexyl-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [21]

[0091]3-n-Hexyl-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[20] (0.20 g, 0.488 mmol) was dissolved in CH₃OH (15 mL) and 10% Pd/C(0.050 g) was added under N₂. A few drops of HCl were added and thereaction mixture was hydrogenated on a parr-hydrogenator at 50 psiovernight and the catalyst was filtered off using celite. The filteratewas evaporated and water (15 mL) was added and basified using 10% NaOH.The basic solution was extracted with CH₂Cl₂ (2×25 mL) and the combinedextracts were washed with water, brine and dried (MgSO₄). The CH₂Cl₂ wasremoved under reduced pressure to give a yellow oil which was purifiedby mplc using CH₂Cl₂:CH₃OH (9:1) as eluent to give 0.11 g (70%) oftheproduct as a colorless oil which darkened rapidly. The oil was convertedinto its oxalate salt, mp. 110-111° C. (EtOAc-CH₃OH). ¹H NMR (CDCl₃)d:0.83-0.89 (m, 2H, CH₂), 1.21-1.31 (m, 9H, CH₂), 2.36-2.40 (t, J=6 Hz,2H, CH₂), 2.56-2.61 (t, J=6 Hz, 2H, CH₂), 3.49 (bs, 2H, CH₂), 3.74 (bs,2H, CH₂), 4.03 (bs, 2H, CH₂), 7.11-7.54 (m, 7H, Ar—H). Anal. Calcd. For(C₂₃H₂₉N.C₂H₂O₄.0.25 H₂O): C, 72.52; H, 7.66; N, 3.38. Found. C, 72.29;H, 7.55; N, 3.15.

Example 9

[0092] Synthesis of3-(3-Phenylpropyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene[23]

[0093] Compound [23] was synthesized as depicted in Scheme 9 and asdescribed below. Referring to Scheme 9, reagents and conditions were asfollows: (a) allyl benzene, 9-BBN, PdCl₂(dppf), K₃PO₄, anhyd. THF (b)10% Pd/C, CH₃OH, HCl

[0094]3-(3-Phenylpropyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[22]

[0095] An oven dried flask equipped with a septum inlet and condenserwas flushed with N₂ and charged with a soln. of 9-BBN (2.15 mL, 1.079mmol, 0.5 M soln.), cooled to 0° C. and allyl benzene (0.142 mL, 1.079mmol) was added via syringe. The mixture was brought to room temperatureand stirred (8 hr.). To the prepared BBN soln. was added K₃PO₄ (0.312 g,1.471 mmol), PdCl₂(dppf) (0.020 g, 5 mol %) and 3-Trifluoromethanesulfonyloxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19](0.48 g, 0.980 mmol) in anhydrous THF (10 mL). The reaction mixture washeated at reflux overnight, cooled and water (20 mL) was added. Thereaction mixture was then extracted with EtOAc (3×25 mL). The combinedEtOAc extracts were washed with water, brine and dried (MgSO₄). Thesolvent was removed under reduced pressure to give a dark brown oil,which was purified by mplc using pet. Ether-EtOAc (9:1) as eluent togive 0.22 g (52%) of the product as an yellow oil. The oil was convertedinto its oxalate, mp. 137-138° C. (EtOAc-CH₃OH). ¹H NMR (DMSO-d₆)d: 1.55(bs, 4H, CH₂), 2.47 (s, 4H, CH₂), 3.21 (s, 2H, CH₂), 3.38 (s, 2H, CH₂),3.94-3.98 (d, J=12Hz, 2H, CH₂), 4.07 (s, 2H, CH₂). ¹³C NMR (CDCl₃) d:21.61, 25.82, 31.63, 35.57, 48.63, 59.90, 61.83, 70.58, 125.40, 125.96,126.45, 127.82, 128.20, 134.73, 135.12, 137.9, 139.04,142.86, 143.77.Anal. Calcd. For(C₃₃H₃₃N.C₂H₂O₄.H₂O): C, 76.20; H, 6.76; N, 2.53. Found.C, 76.11; H, 6.54; N, 2.94.

[0096]3-(3-Phenylpropyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene[23]

[0097] 3-(3-Phenylpropyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl] -9,10-dihydroanthracene [22] (0.20 g, 0.451 mmol) was dissolved in CH₃OH (15mL) and 10% Pd/C (0.050 g) was added under N₂. A few drops of HCl wereadded and the reaction mixture was hydrogenated on a parr-hydrogenatorat 50 psi overnight and the catalyst was filtered off using celite. Thefilterate was evaporated and water (15 mL) was added and basified using10% NaOH. The basic solution was extracted with CH₂Cl₂ (2×25 mL) and thecombined extracts were washed with water, brine and dried (MgSO₄). TheCH₂Cl₂ was removed under reduced pressure to give a yellow oil which waspurified by mplc using CH₂Cl₂:CH₃OH (9:1) as eluent to give 0.071 g(45%) of the product as a colorless oil which darkened rapidly. The oilwas converted into its oxalate salt, mp. 81-82° C. (EtOAc-CH₃OH). ¹H NMR(DMSo-d₆)d: 1.57-1.71 (bd, 4H, CH₂), 2.38 (s, 2H, CH₂), 2.47 (s, 2H,CH₂), 3.38 (s, 2H, CH₂), 3.77 (s, 2H, CH₂), 4.07 (s, 2H, CH₂), 7.27-7.52(bm, 7H, Ar—H). Anal. Calcd. For (C₂₆H₂₇N.C₂H₂O₄.2H₂O): C, 70.12; H,6.93; N, 2.92. Found. C, 69.45; H, 6.34; N, 3.66.

Example 10

[0098] Synthesis of3-(3-Phenyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene [25]

[0099] Compound [25] was synthesized as depicted in Scheme 10 and asdescribed below. Referring to Scheme 10, reagents and conditions were asfollows: (a) Phenyl boronic acid, [(C₆H₅)₃P]₄Pd, K₂CO₃, anhyd. toluene(b) 10% Pd/C, CH₃OH, HCl.

[0100]3-(3-Phenyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[24]

[0101] An oven dried flask equipped with a septum inlet and condenserwas flushed with N₂ phenyl boronic acid (0.25 g, 2.043 mmol)3-Trifluoromethane sulfonyloxy-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene [19](0.48 g, 0.980 mmol) and K₂CO3(0.282 g, 2.04 mmol) were added followedby anhydrous toluene (15 mL). [(C₆H₅)₃P]₄Pd (0.035 g, 3 mol %) was addedimmediately and the reaction mixture was heated at 90° C. for 4 hr. Thereaction mixture was then cooled to room temperature and diluted withEtOAc (25 mL) and washed with satd. NaHCO₃ soln., water, brine and dried(MgSO₄). The solvent was removed under reduced pressure to give a darkbrown oil, which was purified by mplc using pet. ether as eluent to give0.235 g (58%) of the product as a colorless oil. The oil was convertedinto its oxalate, mp. 138-139° C. (EtOAc-CH₃OH). ¹H NMR (CDCl₃)d:2.33-2.44 (m, 2H, CH₂),2.46-3.17 (m, 4H, CH₂), 3.75-3.78 (d, J=9 Hz, 2H,CH₂), 4.02-4.10 (m, 2H, CH₂), 7.12-7.84 (m, 17H, Ar—H). ¹³C NMR (CDCl₃)d: 35.92, 41.66, 49.79, 54.58 60.32, 67.02. Satisfactory elementalanalyses could not be obtained.

[0102] 3-(3-Phenyl)-9,9-[spiro-3′-pyrrolidinyl]-9,10-dihydroanthracene[25]

[0103]3-(3-Phenyl)-9,9-[spiro-3′-(n-benzyl)-pyrrolidinyl]-9,10-dihydroanthracene[24] (0.25 g, 0.622 mmol) was dissolved in CH₃OH (15 mL) and 10% Pd/C(0.10 g) was added under N₂. A few drops of HCl were added and thereaction mixture was hydrogenated on a parr-hydrogenator at 50 psi (4days) and the catalyst was filtered off using celite. The filterate wasevaporated and water (15 mL) was added and basified using 10% NaOH. Thebasic solution was extracted with CH₂Cl₂ (2×25 mL) and the combinedextracts were washed with water, brine and dried (MgSO₄). The CH₂Cl₂ wasremoved under reduced pressure to give a yellow oil which was purifiedby mplc using CH₂Cl₂:CH₃OH (9:1) as eluent to give 0.081 g (42%) of theproduct as a colorless oil which darkened rapidly. The oil was convertedinto its fumarate salt, mp. 129-130° C. (EtOAc-CH₃OH). ¹H NMR(DMSO-d₆)d: 2.35-2.39 (t, J=6Hz, 2H, CH₂), 3.33-3.3 (t, J=6 Hz, 2H,CH₂), 3.78 (s, 2H, CH₂), 4.02-4.04 (d, J=6 Hz, 2H, CH₂), 6.51 (s, 2H,CH=CH), 7.27-7.71 (m, 12H, Ar—H). ¹³C NMR (CDCl₃) d: 35.92, 46.92,51.71, 58.88, 123.83, 126.26, 126.87, 127.54, 128.56, 135.99, 136.83,138.86, 140.55, 141.22, 141.90. Anal. Calcd. For (C₂₃H₂₁N.C₄H₄O₄.H₂O) :C, 72.16; H, 6.22; N, 3.08. Found. C, 71.62; H, 6.19; N, 2.84.

Example 11

[0104] Synthesis of Spiro[xanthenyl]-9,3′-pyrrolidine [30]

[0105] Compound [30] was synthesized as depicted in Scheme 11 and asdescribed below. Referring to Scheme 11, reagents and conditions were asfollows: (a) POCl₃, reflux, 45 min, (b) n-BuLi, BrCH₂COOC₂H₅, Et₂O,reflux, (c) 10% Pd/C, CH₃OH, HCl, (d) Borane-THF/THF; 6.0M HCl.

[0106] 9H-Xanthene-9-carbonitrile [27]

[0107] POCl₃ (25 mL) was added to crystalline 9H-Xanthene-9-carboxamide[26] (1.5 g, 6.65 mmol) while stirring. The solution was then heated atreflux (45 min), when TLC showed complete absence of starting material.The solution was then poured into a mixture of crushed ice and NH₄OHwith vigorous stirring. The solution was stirred (15 min) and excess ofNH₄OH was added to keep the solution alkaline. The solid formed wasextracted with ether (3×50 ml). The combined ether extracts were washedwith water and brine, dried (MgSO₄) and evaporated under reducedpressure to give an yellow oil which crystallized immediately. Theproduct was purified by mplc using pet. ether: acetone (8:2) as eluentto give 1.2 g (87%) 9H-Xanthene-9-carbonitrile as colorless needles, mp97-98° C. (EtOH).

[0108] (9-Cyano-9H-xanthen-9-yl)-acetic acid ethyl ester [28]

[0109] 9H-Xanthene-9-carbonitrile [27] (1.0 g, 4.825 mmol) was dissolvedin anhydrous Et₂O and cooled in an icebath. n-Butyl lithium (1.93 mL,6.75 mmol. 2.5M soln. in hexanes) was added dropwise over 10 min. withcontinuos stirring. Stirring was continued for 30 min. at the sametemperature and then brought to room temperature. The reaction mixturewas heated at reflux (1 hr), cooled in an icebath and ethyl bromoacetate (0.75 mL, 6.755 mmol) was added dropwise via syringe. Theresulting mixture was heated at reflux (4 h) cooled and filtered. Theresidue was washed with ether (25 mL). Water (25 mL) was added to thefilterate and the organic layer was separated. The aqueous layer wasonce again extracted with ether (25 mL). The combined ether extractswere washed with water and brine, dried (MgSO₄) and evaporated underreduced pressure to give an oil which was purified by mplc using pet.ether: EtOAc (9:1) as eluent to give 0.9 g (64%) of the product as acolorless oil. ¹H NMR (CDl₃)d: 1.04-1.08 (t, J=7.5 Hz, CH₃), 3.01 (s,2H, CH₂), 3.90-3.99 (q, 2H, CH₂), 7.14-7.69 (m, 8H, Ar—H). ¹³C NMR(CDCl₃) d: 13.54, 39.06, 48.47, 60.85, 116.88, 118.90, 119.75, 123.81,127.34, 129.83, 150.30, 166.98.

[0110] Spiro[xanthenyl]-9,4′-pyrrolidin-2′-one [29]

[0111] A mixture of (9-Cyano-9H-xanthen-9-yl)-acetic acid ethyl ester[28] (0.50 g, 1.70 mmol), 10% Pd/C (0.15 g) in methanol (40 mL) and HCl(1 mL) was hydrogenated at 50 kg/cm³ (3 days). The catalyst was filteredoff with celite and the solvent was evaporated under reduced pressure togive a white semisolid. Water (25 mL) was added and the solution wasmade basic with 10% NaOH and extracted with EtOAc (3×25 mL). Thecombined EtOAc extracts were washed with water and brine, dried (MgSO₄)and evaporated under reduced pressure to give a colorless oil whichcrystallized immediately on standing. The solid was recrystallized fromCHCl₃-pet.ether to give 0.295 g (69%) of the pure amide as a colorlessneedles, mp 182-183° C. ¹H NMR (CDCl₃)d: 3.02 (s, 2H, CH₂), 3.82 (s, 2H,CH₂), 6.51 (s, 1H, NH), 7.07-7.44 (m, 8H, Ar—H). ¹³C NMR (CDCl₃) d:39.98, 48.50, 60.72, 116.39, 123.70, 125.77, 126.46, 128.31, 149.59,176.10.

[0112] Spiro[xanthenyl]-9,3′-pyrrolidine [30]

[0113] A 1.0M solution of BH₃-THF complex (5.0 ml, 5 mmol) was added at0° C. to a well stirred solution ofSpiro[xanthenyl]-9,4′-pyrrolidin-2′-one [29] (0.25 g, 0.99 mmol) inanhydrous THF (2 mL). The solution was brought to RT and then heated atreflux (8 h), cooled to RT and 6M solution of HCl (4 mL) was addedcautiously to the reaction mixture. The reaction mixture was then heatedat reflux (1 hr), cooled to RT and the solvent was removed under reducedpressure, resulting in a white suspension. Water (20 mL) was added to itand extracted with EtOAc (20 mL). The aqueous phase was then basifledusing 10% NaOH and extracted with Et₂O (3×25 ml). The combined Et₂Oextracts were washed with water and brine, dried (MgSO₄) and the solventwas removed under reduced pressure to give 0.185 g (79%) the amine ascolorless oil. The oil started to darken rapidly and was dissolved inanhydrous acetone and fumaric acid (0.15 g, 1.31 mmol) was added andheated. The solution on cooling gave the fumarate as pale pink powder,which remained on two recrystallizations. mp. 183-184° C. (EtOAc). ¹HNMR (DMSO-d₆)d: 2.26-2.31 (t, J=9 Hz, 2H, CH₂), 3.41-3.45 (t, J=6 Hz,2H, CH₂), 3.64 (s, 2H, CH₂), 6.54 (s, 2H, CH═CH), 7.11-7.64 (m, 8H,Ar—H). ¹³C NMR (DMSO-d₆) d: 44.35, 59.51, 115.96, 123.73, 126.54,127.24, 128.22, 134.87, 140.12, 141.02, 149.87, 167.74, 179.90, 186.56.Anal. Calcd. For (C₁₇H₁₇N.C₄H₄O₄.0.5H₂O): C, 66.28;H, 5.56; N, 3.86.Found. C, 66.41; H, 5.59; N, 3.82

Example 12

[0114] Synthesis of Spiro[thioxanthenyl]-9,3′-pyrrolidine [36]

[0115] Compound [36] was synthesized as depicted in Scheme 12, and asdescribed below. Referring to Scheme 12, reagents and conditions were asfollows: (a) NaBH₄, CH₃OH (b) (i) SOCl₂/Et₂O (ii) CuCN/C₆H₆ (c) n-BuLi,BrCH₂COOC₂H₅, Et₂O, reflux, (c) 10% Pd/C, CH₃OH, HCl, (d)Borane-THF/THF; 6.0M HCl.

[0116] 9H-Thioxanthen-9-ol [32]

[0117] A suspension of thioxanthen-9-one [31] (2 g, 9.42 mmol) inanhydrous CH₃OH (30 mL) was stirred under N₂ and NaBH₄ (1.42 g, 37.68mmol) was added slowly in portions over 15 min. After complete additionthe reaction mixture was heated at reflux (3 hr.) and cooled to roomtemperature. Ice-water was added and the reaction mixture was extractedwith CH₂Cl₂ (3×50 mL). The combined CH₂Cl₂ extracts were washed withwater, brine, dried (MgSO₄). The solvent was removed under reducedpressure to give a yellow solid, which was recrystallized from pet.etherto give 1.87 g (93%) of the alcohol as pale yellow needles, mp 104-105°C.

[0118] 9H-Thioxanthene-9-carbonitrile [33]

[0119] A suspension of 9H-Thioxanthen-9-ol [32] (2.14 g, 9.98 mmol) inanhydrous Et₂O (20 mL) under N₂ and SOCl₂ (0.8 mL, 11.48 mmol) was addedwith caution via syringe with stirring at 0-5° C. The alcohol dissolvedbefore a white solid began to separate. After stirring (1 hr.) at roomtemperature, the solvent was removed under reduced pressure and C₆H₆ (10mL) was added and solvent removed to dryness again. All manipulationswere performed with rigorous exclusion of air. Anhydrous C₆H₆ (20 mL)and CuCN powder (1.79 g, 19.97 mmol) were added and the suspension wasstirred at reflux (4 hr.).The reaction mixture was filtered while hotand the residue was washed with hot C₆H₆ (50 mL). The filterate wasevaporated to give a crystalline residue containing thioxanthene andthioxanthen-9-one as well as the desired nitrile. One recrystallizationsfrom hexane removed thioxanthene and one recrystallizations from2-propanol removed most of the thioxanthen-9one to provide 1.3 g (59%)of the pure nitrile, mp. 97-98° C.

[0120] (9-Cyano-9H-thioxanthen-9-yl)-acetic acid ethyl ester [34]

[0121] 9H-thioxanthene-9-carbonitrile [33] (1.20 g, 5.37 mmol) wasdissolved in anhydrous Et₂O and cooled in an icebath. n-Butyl lithium(2.14 mL, 5.37 mmol, 2.5M soln. in hexanes) was added dropwise over 10min. with continuous stirring. Stirring was continued for 30 min. at thesame temperature and then brought to room temperature. The reactionmixture was heated at reflux (1 hr), cooled in an icebath and ethylbromo acetate (0.83 mL, 7.52 mmol) was added dropwise via syringe. Theresulting mixture was heated at reflux (4 h) cooled and filtered. Theresidue was washed with ether (25 mL). Water (25 mL) was added to thefilterate and the organic layer was separated. The aqueous layer wasonce again extracted with ether (25 mL). The combined ether extractswere washed with water and brine, dried (MgSO₄) and evaporated underreduced pressure to give an oil which was purified by mplc using pet.ether: EtOAc (9:1) as eluent to give 0.97 g (59%) of the product as acolorless oil. ¹H NMR (CDCl₃)d: 1.08-1.12 (t, J=6 Hz, CH₃), 3.08 (s, 2H,CH₂), 3.95-4.03 (q, 2H, CH₂), 7.31-8.00 (m, 8H, Ar—H). ¹³C NMR (CDCl₃)d: 38.49, 47.63, 60.76, 118.91, 127.00, 127.24, 127.80, 128.15, 130.73,130.98, 167.66.

[0122] Spiro[xanthenyl]-9,4′-pyrrolidin-2′-one [35]

[0123] A mixture of(9-Cyano-9H-thioxanthen-9-yl)-acetic acidethyl ester[34] (0.50 g, 1.61 mmol), 10% Pd/C (0.15 g) in methanol (40 mL) and HCl(1 mL) was hydrogenated at 50 kg/cm³ (3 days). The catalyst was filteredoff with celite and the solvent was evaporated under reduced pressure togive a white semisolid. Water (25 mL) was added and the solution wasmade basic with 10% NaOH and extracted with EtOAc (3×25 mL). Thecombined EtOAc extracts were washed with water and brine, dried (MgSO₄)and evaporated under reduced pressure to give a colorless oil whichcrystallized immediatelyon standing. The solid was recrystallized fromCHCl₃-pet.etherto give 0.32 g (74%) of the pure amide as a white solid,mp 178-179° C. ¹H NMR (CDCl₃)d: 3.19 (s, 2H, CH₂), 3.73 (s, 2H, CH₂),6.13 (bs, 1H, NH), 7.22-7.53 (m, 8H, Ar—H). ¹³C NMR (CDCl₃) d: 49.60,53.15, 124.69, 126.68, 127.61, 133.32, 137.72, 176.06.

[0124] Spiro[thioxanthenyl]-9,3′-pyrrolidine [36]

[0125] A 1.0M solution of BH₃-THF complex (3.75 ml, 3.75 mmol) was addedat 0° C. to a well stirred solution ofspiro[thioxanthenyl]-9,4′-pyrrolidin-2′-one [35](0.2 g, 0.74 mmol) inanhydrous THF (2 mL). The solution was brought to RT and then heated atreflux (8 h), cooled to RT and 6 M solution of HCl (4 mL) was addedcautiously to the reaction mixture. The reaction mixture was then heatedat reflux (1 hr), cooled to RT and the solvent was removed under reducedpressure, resulting in a white suspension. Water (20 mL) was added to itand extracted with EtOAc (20 mL). The aqueous phase was then basifiedusing 10% NaOH and extracted with Et₂O (3×25 ml). The combined Et₂Oextracts were washed with water and brine, dried (MgSO₄) and the solventwas removed under reduced pressure to give 0.092 g (49%) the amine ascolorless oil. The oil started to darken rapidly and was dissolved inanhydrous acetone and converted into its oxalate, mp. 169-170° C.(EtOAc). ¹H NMR (DMSO-d₆)d: 2.74 (bs, 2H, CH₂), 3.39 (bs, 2H, CH₂), 3.79(s, 2H, CH₂), 7.36 (bs, 4H, Ar—H), 7.65 (bs, 4H, Ar—H). ¹³C NMR(DMSO-d₆) d: 24.64, 50.02, 51.38, 124.83, 127.02, 133.32, 137.19,163.90, 185.34. Anal. Calcd. For(C₁₆H₁₅NS.C₂H₂O₄.0.25H₂): C, 62.14; H,5.07; N, 4.02. Found. C, 61.90; H, 4.92; N, 3.86

Example 13

[0126] Affinity of Compounds for 5-HT2A Serotonin Receptor

[0127] Binding assays were conducted in which the affinity of each ofthe compounds of interest for the 5-HT_(2A) serotonin receptor wastested. Assays were conducted with the 5-HT_(2A) receptor in bufferconsisting of 50 mM Tris-Cl, 0.5 mM EDTA, 5 mM MgCl₂, pH=7.4. The5-HT_(2A) affinity determinations used ³H-ketanserin as the radioligandand spiperone (Kd=0.8 nM) as the reference compound.

[0128] Binding assays were also conducted in which the affinity ofselected compounds of interest for the H₁ histamine receptor was tested.Assays were conducted with the H₁ receptor in buffer consistion of 50 mMTris-Cl, 0.5 mM EDTA, pH=7.4. The H₁ determinations used ³H-pyrilamineas the radioligand with chlorpheniramine as the reference compound.

[0129] The results are given in Table 2. TABLE 2 Affinity of SelectedSPAN Derivatives for 5-HT_(2A) and H₁ Receptors 5-HT_(2A) H₁ Compound Ki(nM) Ki (nM) 5 3.8 8.5 23 3.5 — 17 3.7 40 21 6 1600 19 9.2 — 25 18 — 646 — 7 220 — 22 998 — 16 1000 74 20 2030 — 18 330 — 12 68 — 30 40 51 365 6

[0130] While the invention has been described in terms of its preferredembodiments, those skilled in the art will recognize that the inventioncan be practiced with modification within the spirit and scope of theappended claims. Accordingly, the present invention should not belimited to the embodiments as described above, but should furtherinclude all modifications and equivalents thereof within the spirit andscope of the description provided herein.

REFERENCES

[0131] Bordwell, F. G., Hughes, D. L. 1983, J. Org. Chem. 48 (13)2216-2222.

[0132] Glennon, R. A., Dukat, M., El-Bermawy, M, Law, H, de los Angeles,J, Teitler, M, King, A and Herrick-Davis, K. 1994. J. Med. Chem.37:1929-1935.

[0133] Glennon, R A, Naiman, N A, Peirson, M E, Smith, J D, Ismaiel, AM, Titeler, M and Lyon, R A. 1989. J. Med. Chem., 32:1921.

[0134] Roth, B L, Craigo, S C, Choudhary, A U, Monsma, F J, Shen, Y,Miltzer, H Y, Sibley, D R. 1994, J. Pharm. Exp Ther. 268: 1403.

[0135] Vaganova, T. A., Panteluva, E. V., Tananakin, A. P., Steingarts,V. D., Bilkis, I. I. 1994, Tetrahedron 50 (33) 10011-10020.

We claim:
 1. A compound having the formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀ alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; and —SO₂—.
 2. The compound of claim 1 wherein R1is selected from the group consisting of —H, —CH₂CH₂CH₂Ph, —OCH₃,—CH₂(CH₂)₄CH_(3,) phenyl, and —OH.
 3. The compound of claim 1 wherein R2is selected from the group consisting of —H, —CH₃ and CH₂Ph.
 4. Thecompound of claim 1 wherein X is selected from the group consisting of—CH₂—, —C(CH₃)₂—, —O— and —S—.
 5. A compound having the formula


6. A compound having the formula


6. A compound having the formula


7. A compound having the formula


8. A compound having the formula


9. A compound having the formula


10. A compound having the formula


11. A compound having the formula


12. A compound having the formula


13. A compound having the formula


14. A compound having the formula


15. A compound having the formula


16. A pharmaceutical composition comprising, a compound of formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀ alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; and —SO₂—, and a pharmaceutically acceptablecarrier.
 17. The pharmaceutical composition of claim 16 wherein R1 isselected from the group consisting of 13 H, —CH₂CH₂CH₂Ph, —OCH₃,—CH₂(CH₂)₄CH₃ and —OH.
 18. The pharmaceutical composition of claim 16wherein R2 is selected from the group consisting of —H, —CH₃ and CH₂Ph.19. The pharmaceutical composition of claim 16 wherein X is selectedfrom the group consisting of —CH₂—, —C(CH₃)₂—, —O— and —S—.
 20. A methodof treating a condition caused by abnormal serotonin activity in apatient in need thereof, comprising the step of administering a compoundof formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀ alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; and —SO₂—, in a quantity to ameliorate symptomsof said condition in said patient.
 21. The method of claim 20 wherein R1is selected from the group consisting of —H, —CH₂CH₂CH₂Ph, —OCH₃,—CH₂(CH₂)₄CH₃ and —OH.
 22. The method of claim 20 wherein R2 is selectedfrom the group consisting of —H, —CH₃ and CH₂Ph.
 23. The method of claim20 wherein X is selected from the group consisting of —CH₂—, —C(CH₃)₂—,—O— and —S—.
 24. The method of claim 20 wherein said condition isselected from the group consisting of depression, anxiety,schizophrenia, schizoaffective disorder, an eating disorder, and a sleepdisorder.
 25. The method of claim 20 wherein said compound is anantagonist of 5HT₂ serotonin receptors.
 26. The method of claim 20wherein said compound is an antagonist of both 5HT₂ receptors and H1receptors.
 27. A method of blocking a 5HT₂ receptor in a patient in needthereof, comprising the step of administering to said patient a compoundof formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C1-C₁₀ alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; and —SO₂—, in a quantity to sufficient to blocksaid 5HT₂ receptor.
 28. A method of blocking an H1 receptor in a patientin need thereof, comprising the step of administering to said patient acompound of formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀ alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; and —SO₂—, in a quantity to sufficient to blocksaid 5HT₂ receptor.
 29. A method of blocking both a 5HT₂ receptor and anH1 receptor in a patient in need thereof, comprising the step ofadministering to said patient a compound of formula

wherein R1 and R2 are selected from the group consisting of —H, —OH,—OCH₃, halogen, aryl, alkylaryl, and substituted or unsubstitutedbranched or unbranched C₁-C₁₀alkyl or alkylaryl, and may be the same ordifferent, and X is selected from the group consisting of a) carbon withtwo —H substituents, b) carbon with one or two lower alkyl substituents,and c) a heteroatom or heteroatomic group selected from the groupconsisting of —O—; —S—; and —SO₂—, in a quantity to sufficient to blocksaid 5HT₂ receptor.